The tumor suppressor protein, p53 is one of the most important cellular defences against malignant transformation. In response to cellular stressors p53 can induce apoptosis, cell cycle arrest or senescence as well as aid in DNA repair. Which p53 function is required for tumor suppression is unclear. The proline-rich domain (PRD) of p53 (residues 58-101) has been reported to be essential for the induction of apoptosis. To determine the importance of the PRD in tumor suppression in vivo we previously generated a mouse containing a 33-amino-acid deletion (residues 55-88) in p53 (mΔpro). We showed that mΔpro mice are protected from T-cell tumors but not late-onset B-cell tumors. Here, we characterize the functionality of the PRD and show that it is important for mediating the p53 response to DNA damage induced by γ-radiation, but not the p53-mediated responses to Ha-Ras expression or oxidative stress. We conclude that the PRD is important for receiving incoming activating signals. Failure of PRD mutants to respond to the activating signaling produced by DNA damage leads to impaired downstream signaling, accumulation of mutations, which potentially leads to late-onset tumors.